A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors
Objective VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. Methods Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. Results Forty-six patients were treated across nine dose levels (12.5–750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. Conclusions VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.
KeywordsFocal adhesion kinase Proline-rich tyrosine kinase-2 Dose-escalation study VS-6063 Defactinib
This study was sponsored by Pfizer Inc. Medical writing support was provided by Andrew Fitton, PhD, of Engage Scientific Solutions, and was funded by Pfizer Inc.
Source of funding
Drs. K. Pierce, B. Houk, and W.G. Roberts are full-time employees of Pfizer Inc. At the time the study was conducted, Dr. S.M. Shreeve was an employee of Pfizer Inc.; currently he is an employee of Janssen Pharmaceutical Companies of Johnson and Johnson. At the time the study was conducted, Dr. S. Pandya was an employee of Beth Israel Deaconess Medical Center; currently she is an employee of Acceleron Pharma. Dr. L. Siu receives research funding for clinical trial support from Pfizer Inc.
Conflict of interest
Dr. G. Shapiro, Dr P. Bedard, Dr J. Infante, Dr A Razak, Dr S. Jones, and Dr J. Cleary have no financial conflicts of interest to declare.
- 13.Shen TL, Park AY, Alcaraz A, Peng X, Jang I, Koni P, Flavell RA, Gu H, Guan JL (2005) Conditional knockout of focal adhesion kinase in endothelial cells reveals its role in angiogenesis and vascular development in late embryogenesis. J Cell Biol 169:941–952. doi: 10.1083/jcb.200411155 PubMedCentralCrossRefPubMedGoogle Scholar
- 14.Golubovskaya VM, Huang G, Ho B, Yemma M, Morrison CD, Lee J, Eliceiri BP, Cance WG (2013) Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide. Mol Cancer Ther 12:162–172. doi: 10.1158/1535-7163.MCT-12-0701 PubMedCentralCrossRefPubMedGoogle Scholar
- 20.Buckbinder L, Crawford DT, Qi H et al (2007) Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc Natl Acad Sci U S A 104:10619–10624. doi: 10.1073/pnas.0701421104 PubMedCentralCrossRefPubMedGoogle Scholar
- 25.Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
- 28.Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG (2005) In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 33:1729–1739. doi: 10.1124/dmd.105.005447 CrossRefPubMedGoogle Scholar
- 29.Soria JC, Gan HK, Arkenau HT (2012) Phase I clinical and pharmacologic study of the focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with advanced solid tumors. J Clin Oncol 30(Suppl):Abst. 3000Google Scholar
- 34.Soria JC, Plummer R, Ranson M, Gan H, Arkenau HT, Zalcman G, Blagden S (2012) Loss of the tumor suppressor Merlin as a potential predictive biomarker of clinical activity for the oral, focal adhesion kinase (FAK) inhibitor GSK2256098 in pts with recurrent mesothelioma. Eur J Cancer 48(Suppl 6):188, Abst. 610 CrossRefGoogle Scholar
- 36.Sood AK, Coffin JE, Schneider GB, Fletcher MS, DeYoung BR, Gruman LM, Gershenson DM, Schaller MD, Hendrix MJ (2004) Biological significance of focal adhesion kinase in ovarian cancer: role in migration and invasion. Am J Pathol 165:1087–1095. doi: 10.1016/S0002-9440(10)63370-6 PubMedCentralCrossRefPubMedGoogle Scholar
- 37.Patel MR, Infante JR, Moore KN, Keegan M, Poli A, Padval M, Jones SF, Horobin J, Burris HA (2014) Phase 1/1b study of the FAK inhibitor defactinib (VS-6063) in combination with weekly paclitaxel for advanced ovarian cancer. J Clin Oncol 32(15 Supplement), Abstract 5521Google Scholar